Oncolytic virotherapy promotes intratumoral T-cell infiltration and improves anti-PD-1 immunotherapy
Blockade of the PD-1/PD-L1 interaction as a monotherapy helps a fraction of melanoma patients. This phase 1b clinical trial of 21 patients tested the addition of a local injection of oncolytic virus carrying GM-CSF to systemic treatment with pembrolizumab. This increased the release of antigen, altered the intratumoral environment, and increased CD8+ T-cell infiltration. The percentage of responders in this trial increased to 62%, with 33% showing a complete response after 72 months.
GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity
Expanding highly functional NK cells ex vivo has been challenging. Inhibition of glycogen synthase kinase 3 (GSK3) in NK-cell cultures expanded with IL-15 was found to increase NK-cell maturation, cytokine production, and ADCC against tumors. When ovarian cancer in a xenograft model was treated with these NK cells, antitumor efficacy was better than with NK cells expanded without the GSK3 inhibitor.
Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression
Pancreatic ductal adenocarcinomas (PDAC) exclude immune infiltrates with fibrotic capsules supported by an immunosuppressive environment. The tumor-associated macrophages (TAMs) maintaining this state are derived from two sources: circulating monocytes and tissue-resident macrophages originating from embryonic progenitors. The resident macrophages proliferated and expanded with PDAC progression. Whereas monocyte-derived TAMs sample tumor antigens, and thus may impact T-cell responses, the tissue-resident macrophages distinctly promoted fibrosis and directly contributed to tumor progression.
Tumor lymphangiogenesis promotes T-cell infiltration and potentiates immunotherapy in melanoma
VEGF-C, which promotes lymphangiogenesis, promotes formation of an immuno-suppressive tumor environment, so the a priori assumption was that blocking it would improve responses to immunotherapies like vaccines. However, VEGF-C was found to increase CCL21 production from lymphatic endothelial cells, which attracts naïve T cells into mouse melanomas that can then be activated. Human melanoma patients with high serum VEGF-C expression were found to have longer progression-free survival.
Two CMTM family members maintain membrane PD-L1 density
Two groups, Burr et al. and Mezzadra et al., sought proteins that regulate the expression or function of PD-L1, which inhibits T-cell activation when bound to PD-1 on T cells. Mezzadra did an unbiased haploid screen of IFNγ-induced HAP1 cells and identified CMTM6 and CMTM4. Burr used a CRISPR/Cas9 screen and also identified CMTM6. CMTM6 binds to PD-L1 in the endosome and prevents its ubiquitination and degradation, thereby allowing persistent PD-L1 expression.
Mitochondrial priming by CD28
CD28 costimulation of T cells is necessary for T-cell activation and generation of memory T cells, but the mechanisms behind memory formation are unclear. CD28 induced the fatty acid oxidation pathway necessary for the mitochondrial adaptations, such as elongation and cristae remodeling. These changes are needed to support the reserve energy-generating capacity required for future rapid and effective memory T-cell recall responses.